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Clinical Relevance: Contrast sensitivity plays an important role in the comprehensive assessment of visual function; however, measurement with standard eye charts can be affected by age and optical abnormality., Background: This study describes a novel chart-based test of letter contrast sensitivity (CS) in luminance noise (the Illinois Eye and Ear Noise CS test), defines normal reference ranges, estimates test-retest repeatability, and assesses the effects of age and simulated optical abnormalities., Methods: Seventy-five individuals with normal visual function (age 18-85 years) participated. Subjects identified letter optotypes that spanned a broad contrast range (0.9% to 59.6%) printed in a book-based test. Letters were presented against a grey background (no-noise condition) and in luminance noise that consisted of light and dark checks (noise condition). A subset of 10 subjects repeated the test to define short-term variability and performed the test under three additional conditions: simulated cataract, +2.00D defocus, and low room illuminance., Results: In the no-noise condition, CS was independent of age (mean log CS of 1.74) until approximately 54 years, and declined for older subjects (CS loss of 0.1 log unit/decade). CS measured in noise was independent of age across the range of ages tested (mean log CS of 0.91). The 95% limits of agreement for test-retest repeatability was 0.19 log units. Simulated cataract, +2.00D defocus, and reduced illumination significantly reduced CS in the no-noise condition (F = 102.6, p  < 0.001), whereas these optical manipulations did not significantly affect CS in noise (F = 2.58, p  = 0.074)., Conclusions: Measurements of CS in luminance noise may be valuable, as these measures are largely independent of age and certain forms of optical degradation. CS measurements in noise may provide useful insight into visual function in patients who have combined neural and optical abnormality, as noise minimises CS loss from optical defects.

Aims/hypothesis: The aim of this study was to explore whether diabetic retinopathy is associated with alterations of the circadian system, and to examine the role of reduced intrinsically photosensitive retinal ganglion cell (ipRGC) function., Methods: Participants with type 2 diabetes, with diabetic retinopathy (n=14) and without diabetic retinopathy (n=9) underwent 24 h blood sampling for melatonin and cortisol under controlled laboratory conditions. ipRGC function was inferred from the post-illumination pupil response (PIPR). Habitual sleep duration, efficiency and variability were assessed by actigraphy., Results: Participants with diabetic retinopathy compared to participants without diabetic retinopathy had smaller PIPR (p=0.007), lower 24 h serum melatonin output (p=0.042) and greater day-to-day sleep variability (p=0.012). By contrast, 24 h cortisol profiles, sleep duration and efficiency were similar in both groups. Six individuals with diabetic retinopathy had no detectable dim-light melatonin onset. PIPR correlated with 24 h mean melatonin levels (r=0.555, p=0.007)., Conclusions/interpretation: ipRCG dysfunction in diabetic retinopathy is associated with disruptions of the 24 h melatonin rhythm, suggesting circadian dysregulation in diabetic retinopathy., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Sleep irregularity and variability have been shown to be detrimental to cardiometabolic health. The present pilot study explored if higher day-to-day sleep irregularity and variability were associated with systemic inflammation, as assessed by high-sensitivity C-reactive protein, in type 2 diabetes. Thirty-five patients with type 2 diabetes (mean age 54.3 years, 54.3% female) who were not shift-workers participated. The presence of diabetic retinopathy was determined. The standard deviation of sleep duration and sleep midpoint across all recorded nights were used to quantify sleep variability and regularity, respectively, assessed by 14-day actigraphy. The presence and severity of sleep apnea were assessed using an overnight home monitor. Low-density lipoprotein, haemoglobin A1C and high-sensitivity C-reactive protein were collected. Multiple regression analysis using natural-log-transformed values was performed to establish an independent association between sleep variability and high-sensitivity C-reactive protein. Twenty-two (62.9%) patients had diabetic retinopathy. The median (interquartile range) of high-sensitivity C-reactive protein was 2.4 (1.4, 4.6) mg L -1 . Higher sleep variability was significantly associated with higher high-sensitivity C-reactive protein (r = 0.342, p = 0.044), as was haemoglobin A1C (r = 0.431, p = 0.010) and low-density lipoprotein (r = 0.379, p = 0.025), but not sleep regularity, sleep apnea severity or diabetic retinopathy. Multiple regression analysis showed that higher sleep variability (B = 0.907, p = 0.038) and higher HbA1c (B = 1.519, p = 0.035), but not low-density lipoprotein, contributed to higher high-sensitivity C-reactive protein. In conclusion, higher sleep variability in patients with type 2 diabetes who were not shift-workers was independently associated with higher systemic inflammation, conferring increased cardiovascular risk. Whether sleep interventions to reduce sleep variability can reduce systemic inflammation and improve cardiometabolic health should be investigated., (© 2023 European Sleep Research Society.)

The pattern electroretinogram (PERG) is a localized retinal response evoked by a contrast-reversing pattern, usually a black and white checkerboard, which provides information about macular and retinal ganglion cell function. This document, from the International Society for Clinical Electrophysiology of Vision (ISCEV; www.iscev.org ) presents an updated and revised Standard for clinical PERG testing. This replaces the 2013 and all earlier versions. Minimum protocols for basic PERG stimuli, recording methods and reporting are specified, to promote consistency of methods for diagnosis and monitoring purposes, while responding to evolving clinical practices and technology. The main changes in the updated ISCEV Standard for clinical PERG include expanded guidance about large stimulus fields, stimulus parameters for simultaneous PERG and pattern visual evoked potential recording, baseline drift correction, and use of consistent ambient room lighting. These changes aim to provide a clinically relevant document about current practice which will facilitate good quality recordings and inter-laboratory comparisons., (© 2024. The Author(s).)

Diabetic retinopathy (DR) is one of the most prevalent microvascular diabetic complications. Poor sleep health and obstructive sleep apnea (OSA) are risk factors for diabetes and poor glycemic control. Recent studies have suggested associations between poor sleep health/OSA and DR. Furthermore, there have been suggestions of melatonin dysregulation in the context of DR. We conducted a systematic review and meta-analysis exploring the associations between multidimensional sleep health (duration, satisfaction, efficiency, timing/regularity and alertness), OSA and melatonin with DR. Forty-two studies were included. Long, but not short sleep, was significantly associated with DR, OR 1.41 (95%CI 1.21, 1.64). Poor sleep satisfaction was also significantly associated with DR, OR 2.04 (1.41, 2.94). Sleep efficiency and alertness were not associated with DR, while the evidence on timing/regularity was scant. Having OSA was significantly associated with having DR, OR 1.34 (1.07, 1.69). Further, those with DR had significantly lower melatonin/melatonin metabolite levels than those without DR, standardized mean difference -0.94 (-1.44, -0.44). We explored whether treating OSA with continuous positive airway pressure (CPAP) led to improvement in DR (five studies). The results were mixed among studies, but potential benefits were observed in some. This review highlights the association between poor multidimensional sleep health and DR., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The purpose of this study was to investigate the reason that diabetic retinopathy (DR) is delayed from the onset of diabetes (DM) in diabetic mice. To this end, we tested the hypothesis that the deleterious effects of DM are initially tolerated because endogenous antioxidative defense is elevated and thereby confers resistance to oxidative stress-induced death. We found that this was indeed the case in both type 1 DM (T1D) and type 2 DM (T2D) mouse models. The retinal expression of antioxidant defense genes was increased soon after the onset of DM. In addition, ischemia/oxidative stress caused less death in the retinal vasculature of DM versus non-DM mice. Further investigation with T1D mice revealed that protection was transient; it waned as the duration of DM was prolonged. Finally, a loss of protection was associated with the manifestation of both neural and vascular abnormalities that are diagnostic of DR in mice. These observations demonstrate that DM can transiently activate protection from oxidative stress, which is a plausible explanation for the delay in the development of DR from the onset of DM.

Alzheimer disease (AD) is the most prevalent cause of dementia in the elderly. Although impaired cognition and memory are the most prominent features of AD, abnormalities in visual functions often precede them, and are increasingly being used as diagnostic and prognostic markers for the disease. Retina contains the highest concentration of the essential fatty acid docosahexaenoic acid (DHA) in the body, and its deficiency is associated with several retinal diseases including diabetic retinopathy and age related macular degeneration. In this study, we tested the hypothesis that enriching retinal DHA through a novel dietary approach could ameliorate symptoms of retinopathy in 5XFAD mice, a widely employed model of AD. The results show that 5XFAD mice have significantly lower retinal DHA compared to their wild type littermates, and feeding the lysophosphatidylcholine (LPC) form of DHA and eicosapentaenoic acid (EPA) rapidly normalizes the DHA levels, and increases retinal EPA by several-fold. On the other hand, feeding similar amounts of DHA and EPA in the form of triacylglycerol had only modest effects on retinal DHA and EPA. Electroretinography measurements after 2 months of feeding the experimental diets showed a significant improvement in a-wave and b-wave functions by the LPC-diet, whereas the TAG-diet had only a modest benefit. Retinal amyloid β levels were decreased by about 50% by the LPC-DHA/EPA diet, and by about 17% with the TAG-DHA/EPA diet. These results show that enriching retinal DHA and EPA through dietary LPC could potentially improve visual abnormalities associated with AD., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: To infer rod phototransduction activation and deactivation characteristics in diabetics who have mild or no clinically-apparent retinopathy., Methods: Fifteen non-diabetic controls, 15 diabetics with no clinically-apparent diabetic retinopathy (NDR), and 15 diabetics with mild non-proliferative diabetic retinopathy (MDR) participated. Dark-adapted flash electroretinograms (3.2 to 4.4 log scot td-s) were recorded to assess rod activation. The a-waves were fit with a Gaussian model to derive R mp3 (maximum photoreceptor response amplitude) and S (phototransduction sensitivity). Rod deactivation was assessed with a paired flash paradigm, in which a-waves were measured for two flashes separated by inter-stimulus intervals (ISIs) of 0.125 to 16 s. The ISI needed for the a-wave amplitude of the second flash to recover to 50% of the first flash (t 50 ) was determined. The effect of stimulus retinal illuminance on activation and deactivation was evaluated in a subset of control subjects., Results: Analysis of variance indicated that both diabetic groups had significant log S reductions compared to controls (p < 0.001). Mean S was reduced by approximately 49% and 78% for the NDR and MDR groups, respectively. In contrast, log R mp3 and log t 50 did not differ significantly among the groups (both p > 0.08). Reducing stimulus retinal illuminance significantly reduced S, but did not significantly affect R max or t 50 ., Conclusions: Only phototransduction sensitivity was abnormal in this sample of diabetic subjects. The normal deactivation kinetics suggests that circulating rod current is normal. These findings begin to constrain possible explanations for abnormal rod function in early diabetic retinal disease., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Changes in the full-field flash and flicker electroretinogram (ERG) that accompany normal aging were evaluated in mice. ERGs were recorded from a single cohort of C57BL/6J mice from 5 to 70 weeks of age using conventional techniques. Dark-adapted ERGs were recorded for flash luminances of - 3.0 to 1.5 log cd-s-m -2 ; a- and b-wave amplitude and implicit time (IT) were calculated from these responses. In addition, light-adapted flicker ERGs elicited by sinusoidally modulated light were measured for temporal frequencies of 2 to 31 Hz. Amplitudes and phases were extracted from the flicker responses using Fourier analysis. Linear quantile mixed models were used for statistical comparisons of the effects of age on amplitude and timing. There was a significant decrease in a-wave amplitude (p < 0.001) and b-wave amplitude (p < 0.001) over the 65 week study. From 5 to 70 weeks, the a- and b-wave amplitudes decreased by a factor of approximately 2. There was a small (2-14 ms), but significant (p < 0.001), delay in a- and b-wave IT over the 65 week study. There was also a significant decrease in fundamental amplitude (factor of 1.8, p < 0.001) and second harmonic amplitude (factor of 1.5, p < 0.001) over time. There were no significant age-related effects on the phase of these components (both p > 0.06). These results indicate that age scales the single flash and flicker ERG similarly, reducing response amplitude by a factor of approximately 2, from 5 to 70 weeks, with small or no effect on response timing. These data may be useful for guiding future longitudinal pre-clinical therapeutic studies., (© 2023. The Author(s).)

Background/purpose: Medication-induced ocular toxicity is an important consideration in the differential diagnosis of unexplained visual disturbance. We present a case of visual disturbance after starting treatment with glecaprevir/pibrentasvir (Mavyret), a therapy for Hepatitis C virus approved by the FDA in 2017., Methods: A 50-year-old male with no significant ocular history experienced bilateral visual disturbance, including visual field and acuity loss, shortly after initiating treatment with Mavyret for Hepatitis C. Examination of the anterior and posterior segments was unremarkable, and no abnormalities could be identified on multimodal imaging of the eye and brain, including MRI, SD-OCT, and fundus autofluorescence. Extensive testing for inflammatory, infectious, nutritional, and genetic etiologies for optic neuropathy and retinopathy was negative., Results: Electrophysiology testing was pursued to narrow the broad differential diagnosis. Full-field electroretinography and multi-focal electroretinography detected deficiencies in the rod and cone visual pathways and attenuated electrophysiologic responses in the fovea. Pattern electroretinography and visually-evoked potentials demonstrated macula dysfunction. Taken together, electrophysiologic data suggested diffuse retinal dysfunction, which was most pronounced in the macula., Conclusions: Given the temporal relationship between Mavyret administration and vision loss in our patient, and the absence of an underlying cause after extensive evaluation, we propose that Mavyret may be associated with a toxic occult retinopathy characterized by panretinal dysfunction without clinically apparent structural findings., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The purpose of this study was to define the nature and extent of sensitivity loss using chromatic perimetry in diabetics who have mild or no retinopathy., Methods: Thirty-four individuals with type II diabetes mellitus who have mild nonproliferative diabetic retinopathy (MDR; N = 17) or no diabetic retinopathy (NDR; N = 17) and 15 visually normal, non-diabetic controls participated. Sensitivity was assessed along the horizontal visual field meridian using an Octopus 900 perimeter. Measurements were performed under light- and dark-adapted conditions using long-wavelength (red) and short-wavelength (blue) Goldmann III targets. Cumulative defect curves (CDCs) were constructed to determine whether field sensitivity loss was diffuse or localized., Results: Sensitivity was reduced significantly under light-adapted conditions for both stimulus colors for the NDR (mean defect ± SEM = -2.1 dB ± 0.6) and MDR (mean defect ± SEM = -4.0 dB ± 0.7) groups. Sensitivity was also reduced under dark-adapted conditions for both stimulus colors for the NDR (mean defect ± SEM = -1.9 dB ± 0.7) and MDR (mean defect ± SEM = -4.5 ± 1.0 dB) groups. For both diabetic groups, field loss tended to be diffuse under light-adapted conditions (up to 6.9 dB loss) and localized under dark-adapted conditions (up to 15.4 dB loss)., Conclusions: Visual field sensitivity losses suggest neural abnormalities in early stage diabetic eye disease and the pattern of the sensitivity losses differed depending on the adaptation conditions. Chromatic perimetry may be useful for subtyping individuals who have mild or no diabetic retinopathy and for better understanding their neural dysfunction.

Background and Objective: To characterize rod-pathway function across the visual field using 2-color dark-adapted perimetry (2cDAP) implemented with conventional Octopus 900 Pro perimeters., Patients and Methods: Eighteen visually normal individuals and two retinitis pigmentosa (RP) patients participated. Thresholds were measured under dark-adapted conditions at 15 locations along the horizontal meridian using short (450 nm) and long (610 nm) wavelength stimuli. Threshold differences between the two wavelengths were used to determine rod- vs cone-mediated function., Results: Among controls, peripheral and perifoveal thresholds for the short-wavelength stimulus were approximately 2 log units lower than for the long-wavelength stimulus. Foveal thresholds for the two wavelengths were similar. RP threshold profiles differed considerably from the controls, with normal foveal thresholds and high peripheral thresholds for both wavelengths., Conclusions: 2cDAP can be performed with an unmodified Octopus perimeter to evaluate rod function across the visual field and obtain information that is not available with standard automated perimetry. [ Ophthalmic Surg Lasers Imaging Retina 2022;53:692-696.] .

Genetic disorders that present during development make treatment strategies particularly challenging because there is a need to disentangle primary pathophysiology from downstream dysfunction caused at key developmental stages. To provide a deeper insight into this question, we studied a mouse model of X-linked juvenile retinoschisis, an early-onset inherited condition caused by mutations in the Rs1 gene encoding retinoschisin (RS1) and characterized by cystic retinal lesions and early visual deficits. Using an unbiased approach in expressing the fast intracellular calcium indicator GCaMP6f in neuronal, glial, and vascular cells of the retina of RS1-deficient male mice, we found that initial cyst formation is paralleled by the appearance of aberrant spontaneous neuroglial signals as early as postnatal day 15, when eyes normally open. These presented as glutamate-driven wavelets of neuronal activity and sporadic radial bursts of activity by Müller glia, spanning all retinal layers and disrupting light-induced signaling. This study confers a role to RS1 beyond its function as an adhesion molecule, identifies an early onset for dysfunction in the course of disease, establishing a potential window for disease diagnosis and therapeutic intervention. SIGNIFICANCE STATEMENT Developmental disorders make it difficult to distinguish pathophysiology due to ongoing disease from pathophysiology due to disrupted development. Here, we investigated a mouse model for X-linked retinoschisis, a well defined monogenic degenerative disease caused by mutations in the Rs1 gene, which codes for the protein retinoschisin. We evaluated the spontaneous activity of explanted retinas lacking retinoschisin at key stages of development using the unbiased approach of ubiquitously expressing GCaMP6f in all retinal neurons, vasculature, and glia. In mice lacking RS1, we found that an array of novel phenotypes, which present around eye opening, are linked to glutamatergic neurotransmission and affect visual processing. These data identify a novel pathophysiology linked to RS1, and define a window where treatments might be best targeted., (Copyright © 2022 the authors.)

Purpose: To evaluate spatial and temporal integration across the visual field in individuals with juvenile X-linked retinoschisis (XLRS)., Methods: Nine subjects with XLRS and 10 visually normal individuals participated. Luminance thresholds were measured at 15 locations along the horizontal visual field meridian. Locations were grouped into four regions for analysis: foveal, parafoveal (2°), perifoveal (5°-10°), and peripheral (10°-60°). For spatial integration measurements, stimulus duration was 100 ms, and size ranged from 0.01 to 2.32 deg2 (Goldmann I-V). For temporal integration measurements, stimulus size was 0.15 deg2 (Goldmann III), and duration ranged from 12 to 800 ms. The effect of stimulus size and duration on the subjects' threshold was described using integration models., Results: Luminance thresholds for the XLRS group were more elevated for small targets (2.0×-12.6×) than for large targets (1.25×-3.2×) compared to controls for all locations. Likewise, thresholds for the XLRS group were more elevated for short durations (6.3×) than for long durations (4.0×) in the fovea and parafovea but were similarly elevated at all durations (2.0×-2.5×) in the perifovea and periphery. For both the size and duration experiments, thresholds measured in the fovea, parafovea, and perifovea of XLRS subjects were highly similar to those measured from the peripheral field of the controls., Conclusions: Spatial and temporal integration characteristics of the XLRS fovea, parafovea, and perifovea are similar to those of the normal periphery. The results also indicate that scaling stimulus size equates thresholds for the XLRS and control subjects throughout the visual field, but scaling duration does not.

The electroretinogram (ERG) is a noninvasive, objective technique to evaluate retinal function that has become increasingly important in the study of diabetic retinopathy. We summarize the principles and rationale of the ERG, present findings from recent clinical studies that have used the full-field ERG, multifocal ERG, and pattern ERG to evaluate neural dysfunction in patients with diabetes, and weigh the strengths and limitations of the technique as it applies to clinical studies and management of patients with diabetic retinopathy. Taken together, ERG studies have provided convincing evidence for dysfunction of the neural retina in patients with diabetes, including those who have no clinically-apparent retinal vascular abnormalities. Recent full-field ERG findings have pointed to the intriguing possibility that photoreceptor function is abnormal in early-stage disease. Pattern ERG data, in conjunction with recently developed photopic negative response analyses, indicate inner retina dysfunction. In addition, multifocal ERG studies have shown spatially localized neural abnormalities that can predict the location of future microaneurysms. Given the insights provided by the ERG, it is likely to play a growing role in understanding the natural history of neural dysfunction in diabetes, as well as providing an attractive outcome measure for future clinical trials that target neural preservation in diabetic retinopathy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: To evaluate retinal function in a family presenting with Jalili syndrome due to a previously unreported variant in CNNM4 ., Methods: A family of three sisters with a novel CNNM4 variant, c.482 T > C p.(Leu161Pro), and ten visually normal, age-similar controls participated in this study. The subjects underwent detailed dental examinations and comprehensive ophthalmological examinations that included color vision testing, retinal imaging, and electroretinography. Full-field light- and dark-adapted luminance thresholds were obtained, in addition to light- and dark-adapted measures of the pupillary light reflex (PLR; pupil constriction elicited by a flash of light) across a range of stimulus luminance., Results: Clinical findings of cone dysfunction and amelogenesis imperfecta were observed, consistent with Jalili syndrome. Light-adapted ERGs were non-detectable in CNNM4 subjects, whereas dark-adapted ERGs were generally normal. Full-field luminance thresholds were normal under dark-adapted conditions and were elevated, but measurable, under light-adapted conditions. The CNNM4 subjects had large PLRs under dark-adapted conditions and responses near the lower limit of normal, or slightly subnormal, under light-adapted conditions., Conclusion: CNNM4 variants can result in Jalili syndrome with cone dystrophy and generally preserved rod function. The PLR may be a useful measure for evaluating cone function in these individuals, as robust cone-mediated PLRs were recordable despite non-detectable light-adapted ERGs.

Purpose: To define relationships among contrast sensitivity (CS), equivalent intrinsic noise (Neq; a measure of noise within the visual pathway), and retinal thickness in X-linked retinoschisis (XLRS)., Methods: Nine XLRS and 10 visually-normal subjects participated. CS was measured in the presence and absence of luminance noise. These data were fit with a standard model to estimate Neq and sampling efficiency (an estimate of the ability to use stimulus information). Optical coherence tomography images were obtained to quantify outer nuclear layer (ONL+) and outer segment (OS+) thickness. A linear structure-function model was used to describe the relationship between CS and the product of ONL+ and OS+ thickness., Results: CS in the absence of noise (CS0) for the XLRS subjects ranged from normal to as much as 1.5× below the lower limit of normal. Four of the nine subjects with XLRS had abnormally high Neq, whereas two others had sampling efficiency that was borderline abnormal. Log CS0 for the subjects with XLRS was correlated significantly with log Neq (r = -0.78, P = 0.01), but not with log efficiency (r = 0.19, P = 0.63). CS0 and Neq, but not efficiency, conformed to the linear ONL+ × OS+ structure-function model., Conclusions: The XLRS subjects in this study who had elevated internal noise had abnormally low CS; both internal noise and CS fell within the predicted limits of a structure-function model., Translational Relevance: Internal noise measurements can provide insight into a source of CS loss in some individuals with XLRS.

Purpose: To determine whether dilation status has a clinically meaningful effect on sensitivity in normal subjects undergoing two-color dark-adapted perimetry, which can be useful to assess rod function., Methods: A perimeter measured naturally and pharmacologically dilated scotopic sensitivities using a test grid consisting of 16 points across the horizontal meridian ranging from 60° temporal to 45° nasal using cyan (500 nm wavelength) or red (650 nm wavelength) stimuli. The primary outcome was average overall sensitivity based on dilation status, which was compared using a linear mixed effect model for each color stimuli. A difference of 2 dB or more was considered clinically significant., Results: Twenty-nine eyes from 15 subjects (nine female) ages 23 to 63 with no known retinal pathology were included. Pharmacologically dilated eyes were 0.54 dB (95% confidence interval [CI], 0.05 dB to 1.03 dB; P = 0.032) more sensitive to a red stimulus than naturally dilated eyes, but this was not statistically significant after correction for multiple comparisons. Pharmacologically dilated eyes were 0.03 dB (95% CI, -0.20 dB to 0.14 dB; P = 0.734) less sensitive to a cyan stimulus compared to naturally dilated eyes., Conclusions: These findings show no clinically significant differences in sensitivity of scotopic perimetry in eyes without retinal pathology based on dilation status for both cyan and red stimuli., Translational Relevance: In this study, pharmacological dilation did not have a clinically meaningful effect on sensitivity, suggesting that this is not necessary when using two-color dark-adapted perimetry to assess for rod function.

Purpose: To provide a comprehensive analysis of light- and dark-adapted luminance thresholds and their associations with retinal structure in X-linked retinoschisis (XLRS)., Methods: Nine subjects with XLRS and 10 visually-normal individuals participated. Threshold was measured at 15 locations along the horizontal meridian of the visual field at several adaptation levels (5 × 10-5 to 50 cd/m2) after dark-adaptation. The relationship between threshold and adaptation level across the field was described using a standard "threshold-versus-illuminance" model. Optical coherence tomography images were obtained and segmented to quantify outer nuclear layer (ONL+) and outer segment (OS+) thickness. A linear structure-function model was used to describe the relationship between threshold and the product of ONL+ and OS+ thickness., Results: For peripheral field measurements, thresholds were generally normal for most subjects with XLRS. All subjects had perifoveal and parafoveal threshold elevations under dark-adapted and high illuminance conditions, with thresholds at moderate illuminances being closer to normal. For foveal measurements, seven of nine subjects with XLRS had normal dark-adapted thresholds, and all had abnormally elevated high illuminance thresholds. Threshold-versus-illuminance curves in the fovea, parafovea, and perifovea were abnormally steep for subjects with XLRS, appearing similar to the normal peripheral field shape. Under both dark- and light-adapted conditions, threshold was predicted by ONL+ × OS+ thickness at nearly all field locations., Conclusions: Threshold elevation in XLRS is complex, depending on both the adaptation level and the visual field location. The pattern of threshold-versus-illuminance suggests that macular function in XLRS is similar to the periphery of controls.

To characterize rod- and cone-pathway function in the 5xFAD mouse model of Alzheimer's disease (AD) using the full-field electroretinogram (ERG). Dark-adapted (DA; rod-pathway) and light-adapted (LA; cone-pathway) ERGs were recorded from three-month-old 5xFAD and wild type (WT) mice. ERGs were elicited by achromatic flashes (0.01-25 cd-s-m - 2 ). Amplitude and implicit time (IT) of the a-wave, b-wave, and oscillatory potentials (OPs) were calculated according to convention. In addition, the amplitude and IT of the photopic negative response (PhNR) were measured from the LA recordings. Amplitude and IT differences between the 5xFAD and WT groups were evaluated using quantile regression models. Under DA conditions, there were significant differences between the 5xFAD and WT groups in post-receptor function, whereas photoreceptor function did not differ significantly. Specifically, the DA a-wave amplitude did not differ between groups (p = 0.87), whereas the b-wave amplitude was reduced in the 5xFAD mice (p = 0.003). There were significant OP (p < 0.001) and a-wave (p = 0.04) delays, but the a-wave delay may be attributable to a post-receptor abnormality. Under LA conditions, the only 5xFAD abnormalities were in the PhNR, which was reduced (p = 0.009) and delayed (p = 0.04). The full-field ERG can be abnormal in the 5xFAD model of AD, with the greatest effects on post-receptor rod pathway function. These results indicate that retinal electrophysiology may be a useful tool for evaluating neural dysfunction in AD.

Purpose: To compare electrophysiological and pupillometric responses in subjects with cone-rod dystrophy due to autosomal recessive (AR) PROM1 mutations., Methods: Four subjects with AR PROM1 dystrophy and 10 visually normal, age-similar controls participated in this study. Full-field, light- and dark-adapted electroretinograms (ERGs) were obtained using conventional techniques. Full-field, light- and dark-adapted measures of the pupillary light reflex (PLR; pupil constriction elicited by a flash of light) were obtained across a range of stimulus luminance using long- and short-wavelength light. Pupil size as a function of stimulus luminance was described using Naka-Rushton functions to derive P max (maximum response) and s (pupil response sensitivity)., Results: Light-adapted ERGs were non-detectable in all four PROM1 subjects, whereas dark-adapted ERGs were non-detectable in three subjects and markedly attenuated in the fourth. By contrast, each PROM1 subject had light- and dark-adapted PLRs. P max ranged from normal to slightly attenuated under all conditions. Light-adapted s was generally normal, with the exception of two subjects who had abnormal s for the long-wavelength stimulus. Dark adapted s was abnormal for each PROM1 subject for the long-wavelength stimulus and ranged from the upper limit of normal to substantially abnormal for the short-wavelength stimulus., Conclusions: ERG and PLR comparison showed an unanticipated dichotomy: ERGs were generally non-detectable, whereas PLRs were normal for all PROM1 subjects under select conditions. Differences between the measures may be attributed to distinct spatiotemporal summation/gain characteristics., Translational Relevance: These data highlight the potential usefulness of pupillometry in cases where the ERG is non-detectable., Competing Interests: Disclosure: J.C. Park, None; F.T. Collison, None; G.A. Fishman, None; J.J. McAnany, None, (Copyright 2020 The Authors.)

Purpose: Retinitis pigmentosa (RP) is an inherited pigmentary retinal dystrophy where patients experience poor peripheral, night, and eventually central vision. There are statements in the literature which suggest visual acuity loss can progress to total blindness in these patients. This study sought to examine these statements by performing a retrospective analysis of the visual acuity measured in a large cohort of RP patients., Methods: The charts of 1,095 RP patients were reviewed in this retrospective cross-sectional analysis. They included all of the RP patients examined by one of the authors (G.A.F.). Patients with sector RP or a delimited form of this disease were not included. The review was focused on the analysis of patients with 20/200 or worse vision in the better-seeing eye (N = 215)., Results: We determined that 0.46% of the enrolled patients progressed to no light perception in each eye. Ninety-two percent of the 1,095 patients examined were able to read a visual acuity chart. There were 6.8% who saw only hand motion, count fingers, or light perception., Conclusion: No light perception was measured in only 0.46% of patients. Thus, only a very small number of the RP patients in our cohort progressed to total blindness.

Purpose: To evaluate the relationship between microperimetric (MP) sensitivity and retinal thickness measured at co-registered retinal locations in individuals who have mild or no diabetic retinopathy., Methods: Fifty non-diabetic control subjects and 50 type-2 diabetic subjects participated (25 had no clinically apparent DR [NDR] and 25 had mild nonproliferative DR [MDR]). MP sensitivity was measured at 36 retinal locations that were arranged in three concentric rings centered on the fovea (radii of 3°, 6°, and 12°). Optical coherence tomography (OCT) images were obtained, and total retinal thickness (TRT), inner retinal thickness (IRT), and outer retinal thickness (ORT) were quantified from the OCT images at locations that matched the MP measures. Linear quantile mixed models (LQMMs) and linear quantile models (LQMs) were used to compare MP and thickness values for the three subject groups and to quantify structure-function relationships., Results: The statistical models indicated significant TRT and IRT reductions in the NDR and MDR groups, relative to the controls, that were most apparent in the 3° ring. By contrast, ORT was not reduced significantly for either diabetic group. MP sensitivity was reduced significantly within each ring and for both diabetic groups. Despite reductions in both thickness and sensitivity, the structure-function associations were generally weak with borderline statistical significance. For example, a TRT or IRT reduction of approximately 27 µm was predicted to result in approximately 1 dB of MP sensitivity loss for the MDR group ( p = .03 and 0.05, respectively)., Conclusions: The results support previous findings of early retinal neurodegeneration in diabetics who have NDR or MDR. Interestingly, the structural and functional deficits appear to be only weakly associated, suggesting that mechanisms in addition to retinal thinning underlie the functional defects in early-stage DR.

Purpose: To evaluate the nature and extent of functional abnormality in X-linked retinoschisis (XLRS) by comparing three dark-adapted, full-field measures: the electroretinogram (ERG), pupillary light reflex (PLR), and luminance threshold., Methods: ERGs, PLRs (pupil constriction due to light stimulation), and luminance thresholds were measured from seven XLRS subjects and from 10 normally sighted, age-similar controls. ERGs and PLRs were obtained for a range of flash strengths, and these data were fit with Naka-Rushton functions to derive the maximum saturated b-wave (Vmax) and PLR (Pmax) amplitudes. Additionally, semi-saturation constants were obtained for the b-wave (σ) and PLR (s). Values of 1/σ and 1/s provide sensitivity measures. Full-field, dark-adapted luminance thresholds were measured using 465-nm and 642-nm flash stimuli., Results: Vmax and 1/σ were significantly reduced in XLRS compared to the controls (both t ≥ 5.33, P < 0.001). In comparison, Pmax was normal in the XLRS subjects (t = 1.39, P = 0.19), but 1/s was reduced (t = 7.84, P < 0.001). Luminance thresholds for the control and XLRS groups did not differ significantly (F = 3.57, P = 0.08). Comparisons among measures indicated that pupil sensitivity was correlated with luminance threshold for the long- and short-wavelength stimuli (both, r ≥ 0.77, P ≤ 0.04). Correlations among all other measures were not statistically significant., Conclusions: The results indicate that the presumed bipolar cell dysfunction in XLRS, indicated by b-wave abnormalities, has complex downstream effects: Dark-adapted luminance threshold and maximum pupil responses are not significantly affected, but pupil sensitivity is reduced.

Purpose: To determine the relationship between contrast sensitivity (CS) and outer-retina thickness (ORT) in diabetics who have minimal or no diabetic retinopathy (DR)., Methods: Twenty non-diabetic control subjects and 40 type-2 diabetic subjects participated (20 had no clinically apparent DR [NDR] and 20 had mild non-proliferative DR [NPDR]). No subject had a history of treatment for macular oedema. Letter CS, microperimetry (MP) sensitivity and visual acuity (VA) were measured. Letter CS and MP measurements were performed over the central 6° of the visual field. Spectral domain optical coherence tomography (SD-OCT) images were obtained at corresponding locations, outer-retina thickness was quantified, and structure-function relationships were evaluated., Results: Analysis of variance indicated significant letter CS differences among the groups (p < 0.001). Letter CS was reduced significantly for the mild NPDR group (p < 0.001; 33% reduction), but not the NDR group (p = 0.08). There were no significant differences in MP sensitivity or ORT among the groups (both p > 0.10). Nevertheless, Hoeffding's D tests indicated significant associations between ORT and letter CS (p < 0.001) and between ORT and MP sensitivity for the mild NPDR group (p = 0.01). VA was not significantly associated with ORT for either diabetic group (both p > 0.49)., Conclusions: Outer-retina thickness is associated with letter CS and MP sensitivity, but not VA, in mild NPDR. This finding highlights the usefulness of simple letter CS measures and suggests neural dysfunction can occur in the absence of marked structural abnormalities in early-stage DR., (© 2019 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To define the relationship between abnormalities in the activation phase of cone phototransduction and the oscillatory potentials (OPs) of the light-adapted electroretinogram in diabetics who have mild or no retinopathy., Methods: Subjects included 20 non-diabetic controls and 40 type-2 diabetics (20 had no clinically apparent diabetic retinopathy [NDR] and 20 had mild nonproliferative DR). Single flash responses for a series of stimulus retinal illuminances were measured under light-adapted conditions using conventional techniques. The a-waves of the responses were fit with a delayed Gaussian model to derive R mp3 (maximum amplitude of the massed photoreceptor response) and S (phototransduction sensitivity). OPs were extracted from the responses by conventional band-pass filtering., Results: Analysis of variance (ANVOA) indicated that both diabetic groups had significant OP amplitude and S reductions compared to the controls, whereas R mp3 did not differ significantly among the groups. Although log OP amplitude and log R mp3 were significantly correlated for the control subjects for each flash retinal illuminance (all r > 0.49, p < 0.03), log OP amplitude and log R mp3 were not correlated for either diabetic group for any flash retinal illuminance (all r ≤ 0.36, p ≥ 0.13). Log OP amplitude and log S were generally not correlated significantly for the control or diabetic groups., Conclusion: OP amplitude losses do not appear to be related to reduced cone sensitivity in early-stage diabetic retinopathy. This suggests that diabetes may separately affect cone function, as evidenced by cone phototransduction sensitivity losses, and inner-retina function, as evidenced by OP amplitude losses.

Background: Intrinsically photosensitive retinal ganglion cells (ipRGCs) control non-visual light responses (e.g. pupillary light reflex and circadian entrainment). Patients with diabetic retinopathy (DR) show reduced ipRGC function, as inferred by abnormalities in the post illumination pupil response (PIPR). We explored whether ipRGC function in DR is associated with circadian outputs and sleep/wake behavior., Methods: Forty-five participants (15 without diabetes, 15 with type 2 diabetes (T2D) and no DR, 15 with T2D and DR) participated. ipRGC function was inferred from the PIPR (pupil size following stimulus offset). Circadian outputs were melatonin amplitude (overnight urinary 6-sulfatoxymelatonin (aMT6s)) and timing (dim light melatonin onset (DLMO)), and evening salivary cortisol levels. Sleep/wake patterns were measured with wrist actigraphy and insomnia symptoms were assessed subjectively., Results: Patients with T2D and DR had smaller PIPR and lower urinary aMT6s than other groups (p < 0.001). In adjusted regression models, smaller PIPR was associated with lower urinary aMT6s (β = 4.552, p = 0.005). Patients with DR were more likely to have no detectable DLMO (p = 0.049), higher evening salivary cortisol, greater insomnia symptoms and greater sleep variability compared to other groups. Sleep duration, efficiency and rest-activity rhythms were similar., Conclusion: Reduced ipRGC function in DR is associated with circadian dysregulation and sleep disturbances, although a causal relationship cannot be established in this cross-sectional study. Prospective mechanistic and intervention studies examining circadian and sleep health in these patients are warranted.

Purpose: To investigate the Stargardt disease phenotype associated with an unusually common and "extremely hypomorphic" ABCA4 variant, p.N1868I., Methods: The charts of 27 patients with p.N1868I on one allele and a severe/deleterious mutation on the other allele were reviewed. Subjective age of onset, best-corrected visual acuity, and stage of disease were recorded for all 27 patients, 18 of whom had multiple visits. When available, fundus photography, spectral domain optical coherence tomography, fundus autofluorescence, full-field electroretinograms, Goldmann visual fields, and fluorescein angiography were included. Five families with multiple affected members were analyzed., Results: The median age at symptom onset was 41.5 years, and 3 p.N1868I patients had not developed visual symptoms as of the most recent eye examination. Median best-corrected visual acuity in the better-seeing eye at baseline was 20/25, and the median duration from symptom onset to legal blindness was 25 years. The five families described in this study demonstrated clinically significant intrafamilial variability, and affected family members who did not share the p.N1868I variant had relatively more severe phenotypes., Conclusion: This study demonstrates the consistency of foveal sparing, the variation in age at onset, the intrafamilial variability, and the prognosis with regard to visual acuity in p.N1868I-associated Stargardt disease.

Purpose: To evaluate retinal dysfunction in diabetic patients who have mild or no nonproliferative diabetic retinopathy (DR) using the high-frequency flicker electroretinogram., Methods: Light-adapted flicker electroretinograms were recorded from 15 diabetic patients who have no clinically apparent retinopathy, 15 diabetic patients who have mild nonproliferative DR, and 15 nondiabetic, age-equivalent controls. Electroretinograms were elicited by full-field flicker at 2 temporal frequencies, 31.25 and 62.5 Hz, and were recorded using conventional techniques. Amplitude and timing of the flicker responses were compared among the groups and correlated with clinical characteristics including age, acuity, disease duration, and HbA1c., Results: The 31.25-Hz flicker amplitude was slightly, but nonsignificantly, smaller for subjects with no DR and mild nonproliferative DR , compared with the control group (both t < 1.38, P > 0.31); small, nonsignificant response delays for both patient groups were also observed (both t < 1.57, P > 0.12). By contrast, there were significant amplitude reductions for the 62.5-Hz flicker stimulus: mean amplitude was reduced by 32% for subjects with no DR and by 41% for subjects with mild nonproliferative DR (both t > 2.92 and P < 0.01). Response timing at 62.5 Hz did not differ significantly from control for either group (both t < 1.2 and P > 0.39). Electroretinogram amplitude and timing were not correlated significantly with clinical characteristics., Conclusion: The 62.5-Hz flicker electroretinogram is useful for evaluating retinal dysfunction in diabetic patients who have mild or no DR because this response can be significantly reduced. Attenuation of the high-frequency flicker electroretinogram, which is primarily generated by bipolar cells, suggests a relatively early retinal site of neural dysfunction.

Purpose: To evaluate three measures of inner retina function, the pattern electroretinogram (pERG), the photopic negative response (PhNR), and the post-illumination pupil response (PIPR) in diabetics with and without nonproliferative diabetic retinopathy (NPDR)., Methods: Fifteen non-diabetic control subjects and 45 type 2 diabetic subjects participated (15 have no clinically apparent retinopathy [NDR], 15 have mild NPDR, and 15 have moderate/severe NPDR). The pERG was elicited by a contrast-reversing checkerboard pattern, and the PhNR was measured in response to a full-field, long-wavelength flash presented against a short-wavelength adapting field. The PIPR was elicited by a full-field, 450 cd/m 2 , short-wavelength flash. All responses were recorded and analyzed using conventional techniques. One-way ANOVAs were performed to compare the pERG, PhNR, and PIPR among the control and diabetic groups., Results: ANOVA indicated statistically significant differences among the control and diabetic subjects for all three measures. Holm-Sidak post hoc comparisons indicated small, nonsignificant reductions in the pERG (8%), PhNR (8%), and PIPR (10%) for the NDR group compared to the controls (all p > 0.25). In contrast, there were significant reductions in the pERG (35), PhNR (34%), and PIPR (30%) for the mild NPDR group compared to the controls (all p < 0.01). Likewise, there were significant reductions in the pERG (40%), PhNR (32%), and PIPR (32%) for the moderate/severe NPDR group compared to the controls (all p < 0.01)., Conclusion: Abnormalities of the pERG, PhNR, and PIPR suggest inner retina neural dysfunction in diabetics who have clinically apparent vascular abnormalities. Taken together, these measures provide a noninvasive, objective approach to study neural dysfunction in these individuals.

Purpose: To investigate receptor and post-receptor function in KCNV2 retinopathy [cone dystrophy with supernormal rod electroretinogram (ERG)], using the pupillary light reflex (PLR) and the ERG., Methods: Two unrelated patients (1 male and 1 female) with molecularly confirmed KCNV2 retinopathy underwent full-field two-color pupillometry testing in one eye, with monitoring of the stimulated eye by an infrared digital camera. Pupillometry stimuli consisted of 1-s duration, short-wavelength (465-nm, blue) and long-wavelength (642-nm, red) stimuli. Pupillometry intensity series were performed under both a dark-adapted condition and a light-adapted condition (on a 0.76-log cd m -2 blue background). The transient PLR, defined as the maximum constriction following flash onset, was measured under all conditions. The melanopsin-mediated sustained constriction was measured 5-7 s following flash offset for the highest flash luminance presented in the dark. Both patients were also tested in one eye with the full-field ERG, including a dark-adapted intensity series and ISCEV standard stimuli., Results: Dark-adapted PLRs were markedly attenuated or extinguished for low-luminance stimuli, but the responses to higher-luminance blue stimuli were within normal limits. Light-adapted PLRs to blue stimuli were generally within normal limits, exceeding the responses to photopically matched red stimuli. Thus, light-adapted responses were consistent with either rod or S-cone mediation of the PLR. Melanopsin-mediated sustained PLRs were within normal limits. ERG showed the characteristic findings previously reported in this condition. Cone-mediated ERG responses were markedly decreased in amplitude. Rod-mediated ERG responses were absent for low-luminance stimuli (- 3 log cd s m -2 ), but had normal amplitude for stimuli of - 2 log cd s m -2 and above (although none were "supernormal"). The b-wave for the dark-adapted ISCEV standard - 2 log cd s m -2 stimulus was markedly delayed, whereas the b-wave timing was generally normal for higher flash luminances., Conclusions: The abnormalities measured by pupillometry have a similar pattern to the outer-retinal abnormalities measured by ERG in KCNV2 retinopathy. These findings as well as the normal sustained PLR suggest that inner-retinal function may be preserved in KCNV2 retinopathy and highlight the potential for therapies designed to restore outer-retinal function in these individuals.

The flicker electroretinogram (ERG) is typically analyzed in terms of peak-to-trough amplitude and implicit time. However, additional important information may be captured by spectral-domain analysis of the ERG harmonics (responses that occur at multiples of the stimulus frequency). This study describes an approach to analyze the harmonic components of the flicker ERG and its application to patients who have early-stage non-proliferative diabetic retinopathy (NPDR). Of particular interest were the sub-harmonic components occurring at 1.5x and 2.5x the stimulus frequency that produce cycle-to-cycle variation in amplitude termed "period doubling." Twenty visually-normal subjects, 20 diabetic subjects who have no clinically-apparent retinopathy (NDR), and 20 diabetic subjects who have mild NPDR participated. ERGs were recorded in response to sinusoidal flicker (27-63 Hz) and Fourier analysis was performed to extract fundamental and harmonic response amplitudes. Linear quantile mixed models (LQMMs) were used to compare the amplitude of the response components among the three subject groups. Results indicated that the maximum sub-harmonic amplitude occurred in the stimulus frequency range of 33-38 Hz for all subjects. The LQMMs showed a significant sub-harmonic amplitude reduction for the mild NPDR subjects compared to the controls; sub-harmonic amplitude for the NDR subjects did not differ significantly from the controls. In contrast, the fundamental response did not differ among the groups for stimulus frequencies between 33 and 38 Hz. Modeling these results indicated that subharmonic amplitude loss in mild NPDR subjects may be attributed to attenuated feedback occurring early in the retina, possibly at the synapse of cone photoreceptors and OFF bipolar cells., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: To define characteristic ocular features in a group of patients with autosomal recessive (AR) PROM1 cone-rod dystrophy (CRD)., Methods: Three males and one female from three unrelated families were first seen at the ages of 15 to 22 years and diagnosed with CRD. Clinical testing available for review included full-field electroretinogram (ERG) in three patients, as well as near-infrared autofluorescence (NIR-AF), spectral-domain optical coherence tomography (SD-OCT), and color fundus photography in all four patients. Whole exome sequencing (WES) was performed on all cases, and whole genome sequencing (WGS) was performed in two families., Results: WES found compound heterozygous PROM1 variants in one isolated male, plus heterozygous variants in the remaining patients. WGS uncovered deleterious PROM1 variants in these two families. ERG showed markedly reduced cone-isolated amplitudes and variably reduced rod-isolated amplitudes. The dark-adapted combined rod and cone responses demonstrated notably reduced a-wave amplitudes and moderately reduced b-waves, and the resultant waveform resembled the normal rod-isolated response. On fundus examination, oval-shaped macular lesions were observed, as were several small, circular hypoautofluorescent lesions within the posterior pole on NIR-AF. Three patients showed extramacular circular atrophic lesions., Conclusions: The autofluorescence changes, peripheral retinal abnormalities, and ERG findings have not been emphasized in previous reports of AR PROM1, but they became a recognizable phenotype in this cohort of patients. A similar constellation of findings may be observed in CRD due to CDHR1, a functionally related gene. The pattern of abnormalities reported herein may help to focus genetic screening in patients with these findings.

Purpose: To define the nature and extent of cone photoreceptor abnormalities in diabetic individuals who have mild or no retinopathy by assessing the activation phase of cone phototransduction and the flicker ERG in these individuals., Methods: Light-adapted single-flash and flicker ERGs were recorded from 20 diabetic individuals who have no clinically apparent retinopathy (NDR), 20 diabetic individuals who have mild nonproliferative diabetic retinopathy (NPDR), and 20 nondiabetic, age-equivalent controls. A-waves elicited by flashes of different retinal illuminance were fit with a delayed Gaussian model to derive Rmp3 (maximum amplitude of the massed photoreceptor response) and S (phototransduction sensitivity). Fundamental amplitude and phase of ERGs elicited by full-field sinusoidal flicker were obtained across a frequency range of 6 to 100 Hz., Results: ANVOA indicated that both diabetic groups had significant S losses compared with the controls, whereas mean Rmp3 did not differ significantly among the groups. ANOVA also indicated significantly reduced flicker ERG amplitude for frequencies ≥56 Hz for both diabetic groups compared with the controls. Flicker ERG timing (phase) did not differ significantly among the groups. Log Rmp3 + log S was significantly correlated with the patients' high-frequency (62.5 Hz) flicker ERG amplitude loss (r = 0.69, P < 0.001)., Conclusions: The delayed Gaussian a-wave model is useful for characterizing abnormalities in the activation phase of cone phototransduction and can help explain flicker ERG abnormalities in early-stage diabetic retinopathy. Reduced cone sensitivity and attenuated high-frequency flicker ERGs provide evidence for impaired cone function in these individuals.

Purpose: The Boston keratoprosthesis (KPro) is the most commonly used artificial cornea. It has been proven to be successful for severe corneal disease not amenable to keratoplasty. We have observed our patients reporting debilitating glare despite attaining good visual acuities. This motivated us to objectively measure light scatter in eyes with a KPro., Methods: Light scatter was measured in 21 eyes with the Boston type 1 KPro with a VA of 20/150 or better and was compared with 13 healthy control eyes using the Oculus C-Quant device (Arlington, WA). Eyes were also measured using an occluder contact lens., Results: Light scatter (quantified as the logS value) was significantly higher in the KPro group than in the control (2.34 ± 0.15 vs. 1.29 ± 0.17, P < 0.001). The polymethylmethacrylate (PMMA) KPro group (16 eyes, logS 2.49 ± 0.19) but not the titanium group (5 eyes, logS 1.87 ± 0.15) had significantly higher light scattering than the control. The use of an occluder contact lens significantly decreased light scatter in eyes with a PMMA backplate (n = 11, logS 1.71 vs. 2.42, P = 0.028)., Conclusion: This study confirms that intraocular light scatter is increased in KPro eyes. Possibly because of its opaque nature, the titanium backplate model seems to produce less light scatter than does the PMMA model. Occluder contact lenses reduced light scatter significantly in the PMMA KPro and could be a treatment option for symptomatic patients.

Purpose: To assess the nature and extent of non-linear processes in pupil responses using rod- and cone-isolating visual beat stimuli. Methods: A four-primary photostimulating method based on the principle of silent substitution was implemented to generate rod or cone isolating and combined sinusoidal stimuli at a single component frequency (1, 4, 5, 8, or 9 Hz) or a 1 Hz beat frequency (frequency pairs: 4 + 5, 8 + 9 Hz). The component frequencies were chosen to minimize the melanopsin photoresponse of intrinsically photosensitive retinal ganglion cells (ipRGCs) such that the pupil response was primarily driven by outer retinal photoreceptor inputs. Full-field (Ganzfeld) pupil responses and electroretinograms (ERGs) were recorded to the same stimuli at two mesopic light levels (-0.9 and 0 log cd/m 2 ). Fourier analysis was used to derive the amplitudes and phases of the pupil and ERG responses. Results: For the beat frequency condition, when modulation was restricted to the same photoreceptor type at the higher mesopic level (0 log cd/m 2 ), there was a pronounced pupil response to the 1 Hz beat frequency with the 4 + 5 Hz frequency pair and rare beat responses for the 8 + 9 Hz frequency pair. At the lower mesopic level there were few and inconsistent beat responses. When one component modulated the rod excitation and the other component modulated the cone excitation, responses to the beat frequency were rare and lower than the 1 Hz component frequency condition responses. These results were confirmed by ERG recordings. Conclusions: There is non-linearity in both the pupil response and electroretinogram to rod and cone inputs at mesopic light levels. The presence of a beat response for modulation components restricted to a single photoreceptor type, but not for components with cross-photoreceptor types, indicates that the location of a non-linear process in the pupil pathway occurs at a retinal site earlier than where the rod and cone signals are combined, that is, at the photoreceptor level.

Purpose: Diabetes is known to cause alterations in retinal microvasculature and tissue that progressively lead to visual impairment. Optical coherence tomography (OCT) is useful for assessment of total retinal thickening due to diabetic macular edema (DME). In the current study, we determined associations between visual acuity (VA) and retinal layer thickness, reflectance, and interface disruption derived from enface OCT images in subjects with and without DME., Materials and Methods: Best corrected VA was measured and high-density OCT volume scans were acquired in 149 diabetic subjects. A previously established image segmentation method identified retinal layer interfaces and locations of visually indiscernible (disrupted) interfaces. Enface thickness maps and reflectance images of the nerve fiber layer (NFL), combined ganglion cell and inner plexiform layer (GCLIPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), photoreceptor outer segment layer (OSL), and retinal pigment epithelium (RPE) were generated in the central macular subfield. The associations among VA and retinal layer metrics were determined by multivariate linear regressions after adjusting for covariates (age, sex, race, HbA1c, diabetes type, and duration) and correcting for multiple comparisons., Results: In DME subjects, increased GCLIPL and OPL thickness and decreased OSL thickness were associated with reduced VA. Furthermore, increased NFL reflectance and decreased OSL reflectance were associated with reduced VA. Additionally, increased areas of INL and ONL interface disruptions were associated with reduced VA. In subjects without DME, increased INL thickness was associated with reduced VA, whereas in subjects without DME but with previous antivascular endothelium growth factor treatment, thickening of OPL was associated with reduced VA., Conclusions: Alterations in retinal layer thickness and reflectance metrics derived from enface OCT images were associated with reduced VA with and without presence of DME, suggestive of their potential for monitoring development, progression, and treatment of DME.

Purpose: To define the nature and extent of temporal frequency abnormalities in diabetics who have mild or no nonproliferative diabetic retinopathy (NPDR) by using the flicker electroretinogram (ERG)., Methods: Light-adapted flicker ERGs were recorded from 20 diabetics who have no clinically apparent retinopathy, 20 diabetics who have mild NPDR, and 20 nondiabetic, age-equivalent controls. ERGs were elicited by full-field sinusoidal flicker across the temporal frequency range of 6 to 100 Hz and were recorded using conventional techniques. The amplitude and phase of the fundamental and harmonic response components were derived by Fourier analysis and compared among the groups., Results: Analysis of variance indicated that compared with the controls, both patient groups had significant amplitude reductions of the fundamental ERG component for temporal frequencies greater than 56 Hz (all P ≤ 0.03). Modeling the amplitude measurements indicated that both patient groups had significant reductions in the high-frequency response cutoff. Response phase, however, did not differ significantly among the groups at any frequency. The amplitude and phase of the high-frequency harmonics (32-96 Hz) of the patients' responses to a low-frequency stimulus (16 Hz) were normal over the temporal frequency range that the fundamental response was abnormal., Conclusions: Taken together, the diabetics' fundamental amplitude attenuation for rapid flicker combined with their normal high-frequency harmonic responses generated by slow flicker suggest that the likely site of the abnormal temporal filtering occurs prior to the nonlinearity that generates the harmonic components of the ERG, implicating a photoreceptor origin.

Significance: The response of the pupil to a flash of light, the pupillary light reflex (PLR), is an important measure in optometry and in other fields of medicine that is typically evaluated by qualitative observation. Here we describe a simple, portable, iPhone-based pupillometer that quantifies the PLR in real time., Purposes: The purposes of this study were to describe a novel application that records the PLR and to compare its technical capabilities with a laboratory-based infrared (IR) camera system., Methods: Pupil sizes were measured from 15 visually normal subjects (age, 19 to 65 years) using an IR camera system and the Sensitometer test. This test elicits pupillary constriction using the iPhone flash, records pupil size using the camera, and provides measurements in real time. Simultaneous recordings were obtained with the Sensitometer test and IR camera, and two measures were calculated: (1) dark-adapted steady-state pupil size and (2) minimum pupil size after the flash. The PLR was defined as the difference between these two measures. Pupil size was also recorded during the redilation phase after the flash. Bland-Altman analysis was used to assess the limits of agreement between the two methods., Results: Statistically significant correlations between the IR and Sensitometer test measures were found for the PLR (r = 0.91, P < .001) and redilation size (r = 0.65, P = .03). Bland-Altman analysis indicated a mean PLR difference of 6% between these two methods. The PLR limit of agreement was 14%, indicating that 95% of subjects are expected to have IR and Sensitometer test measurements that differ by 14% or less. Bland-Altman analysis indicated a mean redilation size difference of 1% between the two methods; the limit of agreement was 5%., Conclusions: There is excellent agreement between pupil responses recorded using the Sensitometer test and IR camera. The Sensitometer test provides a highly promising approach for simple, portable, inexpensive pupillary measurements.

Oxidative stress is a pathogenic feature in vitreoretinal disease. However, the ability of the inner retina to manage metabolic waste and oxidative stress is unknown. Proteomic analysis of antioxidants in the human vitreous, the extracellular matrix opposing the inner retina, identified superoxide dismutase-3 (SOD3) that localized to a unique matrix structure in the vitreous base and cortex. To determine the role of SOD3, Sod3 -/- mice underwent histological and clinical phenotyping. Although the eyes were structurally normal, at the vitreoretinal interface Sod3 -/- mice demonstrated higher levels of 3-nitrotyrosine, a key marker of oxidative stress. Pattern electroretinography also showed physiological signaling abnormalities within the inner retina. Vitreous biopsies and epiretinal membranes collected from patients with diabetic vitreoretinopathy (DVR) and a mouse model of DVR showed significantly higher levels of nitrates and/or 3-nitrotyrosine oxidative stress biomarkers suggestive of SOD3 dysfunction. This study analyzes the molecular pathways that regulate oxidative stress in human vitreous substructures. The absence or dysregulation of the SOD3 antioxidant at the vitreous base and cortex results in increased oxidative stress and tissue damage to the inner retina, which may underlie DVR pathogenesis and other vitreoretinal diseases., (Copyright © 2018. Published by Elsevier Inc.)

The International Society for Clinical Electrophysiology of Vision (ISCEV) Standard for full-field electroretinography (ERG) describes a minimum procedure, but encourages more extensive testing. This ISCEV extended protocol describes an extension to the ERG Standard, namely the photopic negative response (PhNR) of the light-adapted flash ERG, as a well-established technique that is broadly accepted by experts in the field. The PhNR is a slow negative-going wave after the b-wave that provides information about the function of retinal ganglion cells and their axons. The PhNR can be reduced in disorders that affect the innermost retina, including glaucoma and other forms of optic neuropathy. This document, based on existing literature, provides a protocol for recording and analyzing the PhNR in response to a brief flash. The protocol includes full-field stimulation, a frequency bandwidth of the recording in which the lower limit does not exceed 0.3 Hz, and a spectrally narrowband stimulus, specifically, a red flash on a rod saturating blue background. Suggested flash strengths cover a range up to and including the minimum required to elicit a maximum amplitude PhNR. This extended protocol for recording the PhNR provides a simple test of generalized retinal ganglion cell function that could be added to standard ERG testing.

Purpose: To evaluate explanations for contrast sensitivity (CS) losses in subjects who have mild nonproliferative diabetic retinopathy (NPDR) or no diabetic retinopathy (NDR) by measuring and modeling CS in luminance noise., Methods: Ten diabetic subjects with NDR, 10 with mild NPDR, and 10 age-equivalent nondiabetic controls participated. Contrast threshold energy (Et) was measured for letters presented in the absence of noise (Et0) and in four levels of luminance noise. Data were fit with the linear amplifier model to estimate inferred noise level within the visual pathway (Neq) and sampling efficiency (ability to use stimulus information optimally). Et0, Neq, and efficiency were compared to clinical characteristics., Results: Neq was correlated with Et0 for the diabetic subjects (r = 0.93, P < 0.001) and ranged from normal to 12-times the upper limit of normal. ANOVA indicated significant differences among the subject groups for Et0 and Neq (both F > 11.92, P < 0.001). Et0 and Neq were elevated for the mild NPDR group compared to the control and NDR groups (all t > 3.89, P ≤ 0.001); the NDR and control groups did not differ significantly (all t < 0.61, P > 0.55). There were no significant efficiency differences among the groups (F = 1.29, P = 0.29). Neq was correlated significantly with disease duration, microperimetric sensitivity, and Pelli-Robson CS., Conclusions: Elevated contrast threshold may be associated with increased intrinsic noise in early-stage diabetic subjects. Results suggest that noise-based CS measurements can provide important information about early neural dysfunction in these individuals.

Purpose: To evaluate the relationship between electrophysiological measures of retinal ganglion cell (RGC) function in patients who have idiopathic intracranial hypertension (IIH)., Methods: The pattern electroretinogram (pERG) and photopic negative response (PhNR) were recorded from 11 IIH patients and 11 age-similar controls. The pERG was elicited by a contrast-reversing checkerboard. The PhNR, a slow negative component following the flash ERG b-wave, was recorded in response to a long-wavelength flash presented against a short-wavelength adapting field. The PhNR was elicited using full-field (ffPhNR) and focal macular (fPhNR) stimuli. Additionally, Humphrey visual field mean deviation (HVF MD) was measured and ganglion cell complex volume (GCCV) was obtained by optical coherence tomography., Results: The ffPhNR, fPhNR, and pERG amplitudes were outside of the normal range in 45, 9, and 45% of IIH patients, respectively. However, only mean ffPhNR amplitude was reduced significantly in the patients compared to controls (p < 0.01). The pERG amplitude correlated significantly with HVF MD and GCCV (both r > 0.65, p < 0.05). There were associations between ffPhNR amplitude and HVF MD (r = 0.58, p = 0.06) and with GCCV (r = 0.52, p = 0.10), but these did not reach statistical significance. fPhNR amplitude was not correlated significantly with HVF MD or GCCV (both r < 0.40, p > 0.20)., Conclusions: Although the fPhNR is generally normal in IIH, other electrophysiological measures of RGC function, the ffPhNR and pERG, are abnormal in some patients. These measures provide complementary information regarding RGC dysfunction in these individuals.

Purpose: The pattern electroretinogram (pERG) response reflects, in part, ganglion cell function. However, probing retinal ganglion cell (RGC) function in the mid- and far peripheral retina is difficult with conventional flat-panel pERG stimulus sources. A pattern stimulus source is presented for probing the peripheral retina. Peripheral pERG (ppERG) responses were evaluated versus luminance, reversal rate, and field subtended, and were compared with conventional pERG in healthy eyes., Methods: Eleven normally-sighted subjects were recruited. A hemispherical surface was used to present a reversing checkerboard pattern to the peripheral retina, from approximately 35° to 85° of visual field, in all directions. Responses to stimuli presented to peripheral field sectors (superior, nasal, inferior, temporal) were also recorded. Conventional pERG responses were recorded on the same day. Amplitudes and implicit times of waveform peaks were evaluated., Results: Robust pERG responses from peripheral retina resemble conventional pERG responses but with shorter implicit times and reduced positive component. Responses to high-luminance patterns include high-frequency components resembling flash ERG oscillatory potentials. Negative response component amplitudes increased with increasing pattern luminance, and decreased with increasing reversal rate., Conclusions: Peripheral-field pERG responses are robust and repeatable; the unique response properties reflect differences between central and peripheral retina. Field-sector response ratios can be used to probe for sectoral dysfunction associated with disease., Translational Relevance: The ppERG approach provides direct measurement of proximal retinal function beyond the fields probed by conventional perimetry and pERG, providing access to a relatively under studied part of the retina relevant to early stage glaucoma.

This study evaluated the extent to which different types of luminance noise can be used to target selectively the inferred magnocellular (MC) and parvocellular (PC) visual pathways. Letter contrast sensitivity (CS) was measured for three visually normal subjects for letters of different size (0.8°-5.3°) under established paradigms intended to target the MC pathway (steady-pedestal paradigm) and PC pathway (pulsed-pedestal paradigm). Results obtained under these paradigms were compared to those obtained in asynchronous static noise (a field of unchanging luminance noise) and asynchronous dynamic noise (a field of randomly changing luminance noise). CS was measured for letters that were high- and low-pass filtered using a range of filter cutoffs to quantify the object frequency information (cycles per letter) mediating letter identification, which was used as an index of the pathway mediating CS. A follow-up experiment was performed to determine the range of letter duration over which MC and PC pathway CS can be targeted. Analysis of variance indicated that the object frequencies measured under the static noise and steady-pedestal paradigms did not differ significantly (p ≥ 0.065), but differed considerably from those measured under the dynamic noise (both p < 0.001) and pulsed-pedestal (both p < 0.001) paradigms. The object frequencies mediating letter identification increased as duration increased under the steady-pedestal paradigm, but were independent of target duration (50-800 ms) under the pulsed-pedestal paradigm, in static noise, and in dynamic noise. These data suggest that the spatiotemporal characteristics of noise can be manipulated to target the inferred MC (static noise) and PC (dynamic noise) pathways. The results also suggest that CS within these pathways can be measured at long stimulus durations, which has potential importance in the design of future clinical CS tests.

Purpose: To evaluate the nature and extent of letter contrast sensitivity (CS) deficits in glaucoma patients using a commercially available computer-based system (M&S Smart System II) and to compare the letter CS measurements to standard clinical measures of visual function., Methods: Ninety-four subjects with primary open-angle glaucoma participated. Each subject underwent visual acuity, letter CS, and standard automated perimetry testing (Humphrey SITA 24-2). All subjects had a best-corrected visual acuity (BCVA) of 0.3 log MAR (20/40 Snellen equivalent) or better and reliable standard automated perimetry (fixation losses, false positives, and false negatives <33%). CS functions were estimated from the letter CS and BCVA measurements. The area under the CS function (AUCSF), which is a combined index of CS and BCVA, was derived and analyzed., Results: The mean (± SD) BCVA was 0.08±0.10 log MAR (∼20/25 Snellen equivalent), the mean CS was 1.38±0.17, and the mean Humphrey Visual Field mean deviation (HVF MD) was -7.22±8.10 dB. Letter CS and HVF MD correlated significantly (r=0.51, P<0.001). BCVA correlated significantly with letter CS (r=-0.22, P=0.03), but not with HVF MD (r=-0.12, P=0.26). A subset of the subject sample (∼20%) had moderate to no field loss (≤-6 dB MD) and minimal to no BCVA loss (≤0.3 log MAR), but had poor letter CS. AUCSF was correlated significantly with HVF MD (r=0.46, P<0.001)., Conclusions: The present study is the first to evaluate letter CS in glaucoma using the digital M&S Smart System II display. Letter CS correlated significantly with standard HVF MD measurements, suggesting that letter CS may provide a useful adjunct test of visual function for glaucoma patients. In addition, the significant correlation between HVF MD and the combined index of CS and BCVA (AUCSF) suggests that this measure may also be useful for quantifying visual dysfunction in glaucoma patients.